Genetic variation in fatty acid amide hydrolase (FAAH): Associations with early drinking and smoking behaviors

The endocannabinoid system is involved in reward, motivation, and addictions (Kano, Ohno-Shosaku, Hashimotodani, Uchigashima, & Watanabe, 2009, Parolaro, Vigano’, Realini, & Rubino, 2007). For example, rimonabant, an endocannabinoid CB1 receptor antagonist, prevented alcohol-seeking behaviors in alcohol-naive alcohol-preferring rats (Serra et al., 2001), and CB2 receptor knock-out mice had lower nicotine self-administration than their wild-type counterparts (Navarrete et al., 2013). As part of this system, fatty acid amide hydrolase (FAAH) metabolizes anandamide, a CB1 receptor agonist (Biringer, 2021). In the human FAAH gene, a common missense variant (rs324420; C > A; Pro129Thr) results in reduced FAAH protein stability (Sipe et al., 2002). As such, individuals in the A-group (i.e., C/A or A/A genotypes) have slower activity compared to those in the C-group (i.e., C/C genotype) (Chiang et al., 2004). FAAH variation is associated with drug addiction (Best et al., 2021, Butler and Le Foll, 2020, Haughey et al., 2008, Sloan et al., 2018, Tyndale et al., 2007).

In animals (Basavarajappa et al., 2006, Blednov et al., 2007, Vinod et al., 2007, Zhou et al., 2016) and adult humans (Best et al., 2021, Sloan et al., 2018), there are associations between slow FAAH activity (inferred from FAAH rs324420 genotype in humans) and increased harmful alcohol use. Among young adults aged ∼ 20 (Best et al., 2021) and those aged ∼ 37 (Sloan et al., 2018), those in the A-group reported more drinking days, binge drinking days, and greater alcohol use severity relative to those in the C-group. In post-mortem brain studies, slow activity occurred in the ventral striatum of individuals with alcohol use disorder (AUD) compared to controls (Vinod et al., 2010), but not in the prefrontal cortex (Erdozain et al., 2015). Using PET imaging, patients with AUD had lower FAAH levels across different brain regions compared to controls, even after controlling for FAAH rs324420 genotype (Best et al., 2020).

The association between FAAH variation and smoking is less clear. URB597, a selective FAAH inhibitor, attenuated the rewarding effects of nicotine, nicotine self-administration, and reinstatement of nicotine self-administration following extinction in rats and squirrel monkeys (Scherma et al., 2008, Schindler et al., 2016). Further, URB597 blocked the acquisition of nicotine self-administration in rats without altering self-administration in a progressive ratio paradigm (Forget et al., 2009). In contrast, URB597 produced no decrease in nicotine self-administration in rats, but ARNT14381 (a FAAH inhibitor and dopamine D3 receptor partial agonist) decreased self-administration to a greater extent, suggesting that FAAH inhibition alone may not be sufficient to alter nicotine-seeking behaviors (Lunerti et al., 2022). In human adults, FAAH rs324420 was not associated with regular smoking or nicotine dependence (Tyndale et al., 2007).

Together, animal and adult human data suggest that slow FAAH activity may be associated with increased alcohol consumption, including binge drinking. However, associations with nicotine-seeking behaviors are less clear. As most of the human literature pertains to adults, our aim was to examine the relationships between slow FAAH activity and behaviors related to alcohol consumption and cigarette smoking during adolescence and into young adulthood.

Initially, we examined the probability of past-year binge drinking when the cohort was young adults to replicate previous findings using the same genotype groupings (i.e., A- versus C-group) (Best et al., 2021, Sloan et al., 2018). Next, in Objective 1A, we estimated the association between genotype and time to initiation of alcohol consumption among never-drinkers. In Objective 1B, we estimated the association between genotype and time to attaining monthly, weekly, and daily drinking among adolescent incident (i.e., those who have initiated during the study follow-up) drinkers.

We speculated that the association between FAAH genotype would extend to smoking initiation if it had a general effect on drug initiation among never users. Thus, in Objective 2A, we estimated the association between genotype and time to smoking initiation among never-smokers. In Objective 2B, we explored (and corrected for multiple testing) the association between genotype and time to attaining established (O’Loughlin et al., 2009) early smoking milestones among adolescent incident smokers.

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